Human immunodeficiency virus type 1 (HIV-1) is the causative agent of acquired immune deficiency syndrome (AIDS), the dominant public health problem in our nation. The growth in our understanding of this virus, discovered only in 1983, has been phenomenal. However, serious gaps in our knowledge exist, particularly with regard to certain aspects of the viral replication cycle. Further elucidation of the HIV-1 life cycle may lead to more effective vaccines and antiviral therapies. The goal of this research proposal is to study the replication of HIV-1 at the molecular level. The studies planned in this application will focus on the early events of the viral life cycle, from virus entry into the cell to viral DNA integration into the host cell chromosome. We will investigate the kinetics and efficiency of replication of HIV-1 prior to integration. We will examine the viral proteins and the nature of the substructures which transport the viral DNA from the plasma membrane to the nucleus. We will explore the integration of the HIV-1 DNA by developing an HIV-1 integration system and characterizing the viral preintegrative complex. We will also study the role of the unintegrated viral DNAs in replication and cytopathogenesis. We would like to determine whether these DNAs can be efficient transcriptional templates and thus play a role in the massive overexpression of viral RNA in some infected cells.